Perspectives on Environmental Assessments of Chemicals Used in Consumer Products Bryan W. Brooks...

Perspectives on Environmental Assessments of Chemicals Used in

Consumer Products

Bryan W. BrooksProfessor and Director

Department of Environmental ScienceCenter for Reservoir and Aquatic Systems Research

Institute of Biomedical Studies

Assessment of Environmental Effects

Environmental safety studies generally have a two-fold purpose:

1. Determine whether a chemical produces an effect on a biological system

2. Determine how much of an effect is present

Single species laboratory toxicity tests, microcosms/mesocosms, and field studies are often used to determine thresholds at individual, population or community levels

Assessment of Environmental Effects:Prospective and Retrospective

• New product safety assessments and environmental quality criteria derivation rely on similar model organisms with survival, growth and reproduction endpoints

• Effluent water quality evaluated by whole effluent toxicity tests

algae

+ +

Daphnia fishwww.cefas.co.uk www.cefas.co.uk

What is More Toxic, What is Safer?

De Wolf et al. 2005

Hodge and Sterner 1949

“Read-Across” approaches are often explored for comparative and relative toxicology studies

Acute Toxicity

log

KO

W

1 2 3 4 5 6

1

2

3

4

5

6

2.

3.

4.

1.

QSAR

Acute

Chronic

- Cosm/Chronic SSD

Re

alis

tic(p

redi

ctiv

e)

Co

nse

rvat

ive

(pro

tect

ive)

Simple(data poor)

Complex(data rich)

Uncertaintyunknown

Uncertaintydescribed

Hig

ha

ccu

racy

Low

acc

ura

cy

Ecological Risk AssessmentProspective and Retrospective

Exposure EffectsRISKRISK

Problem Formulation

Risk Characterization

Risk Management

Deterministic Approach:[Exposure] / [Effect] > 1

Weight of Evidence

Uncertainty

Texas Water Resources

www.tpwd.state.tx.us


www.seco.cpa.state.tx.us

Wastewater treatment

Five primary types: activated sludge, oxidation ditch, trickling filter, lagoon, rotating biological contactor


West TexasWest TexasDry climateDry climate

Little vegetationLittle vegetationHigh surface water pHHigh surface water pH

Dry climateLittle vegetationHigher salinity

Higher surface water pH

East TexasEast TexasDifferent geomorphologyDifferent geomorphology

Wetter climateWetter climateGreater vegetationGreater vegetation

Brazos River Watershed

Lower pHGenerally, higher pH

Uncertainties in ERAs of Consumer Products

1. Ionization and pH

Brooks et al 2012 Du et al. in prep

Time (hour)

0 20 40 60 80 100

Con

cent

rati

on (

mg/

kg)

0

100

200

300

400

500

600 pH 7.7pH 8.7

pH Matters: In Streams, In the Lab

Fish Uptake of Diphenhydramine (pKa = 8.9) from Water to Plasma

Dissolved Oxygen (mg/L)

6 8 10 12 14 16

pH

8.6

8.8

9.0

9.2

9.4

9.6

9.8

R2= 0.782; p < 0.0001

Relationship between pH andDO, Lake Conroe, Texas



Valenti et al. 2009. ET&C


Nakamura et al. (2008)

↑ nonionized, ↑ BCF

TIme (h)

0 10 20 30 40

Su

rviv

ors

hip

(%

)

0

20

40

60

80

100

pH 6.5pH 7.5pH 8.5

Acute results

pH

6 7 8 9

log

LC

50 v

alu

e

10

100

1000

97.0

91.547.02

r

xy

Growth results

pH

6 7 8 9

log

EC

10 v

alu

e

10

100

1000

99.0

1.652.02

r

xy


N & P range in standard Lemna media:

N and P conditions variable, dissimilar from surface waters

Medium N (mg L-1) P (mg L-1) Molar N:PHoagland A 280 155 4Hutner B 127 93 3Steinberg C 84 46 820X-AAP D 84 3.7 50SIS E 14 2.4 13A ASTM, B Brain & Solomon, C Mkandawire and

Dudel D EPA, E OECD ,

2. Nutrient stoichiometry and concentrations affect toxicity


Fulton et al. 2009. ET&C

2. Nutrient influences on triclosan toxicity


Day 7 Day 14

Fulton et al. 2009. ET&C

2. Nutrient influences on triclosan toxicity


3. Chirality

Enantiomers can significantly differ in:• Biodegradation• Selectivity for receptors, transporters, and/or enzymes • Type of effect(s)• Potency• Rate of metabolism & structure of metabolites• Rate of uptake and excretion

Introduces Uncertainty in…

EXPOSURE & TOXICITY


CF3

O

HN

Ph

H

F3C

O

NH

Ph

H

S-fluoxetine R-fluoxetine

Feeding rate EC10

R-fluoxetine 16.1µg/L

S-fluoxetine 3.7 µg/L

Growth EC10

R-fluoxetine 132.9 µg/L

S-fluoxetine 14.1 µg/L

5-HT

NPY

Feeding

Growth

Stanley et al 2007 Chemosphere

Comparative Toxicology and Chirality

Connors et al. In prep.

Enantiomer-Specific Metabolism Differs from Racemate

Rainbow trouth model: S9 substrate depletion kineticsTime (min)

0 10 20 30 40 50 60 70

log

Con

cent

ratio

n (u

mol

/L)

-1.6

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

rac-PropranololS-Propranolol R-Propranolol

Intrinsic Clearance Rates(mL/hr/mg)

Rac-Propranolol 2.89R-Propranolol 0.66S-Propranolol 1.91

Comparative Toxicology and Chirality

O N CD3

D3C

OH

D

Stanley and Brooks. 2009. IEAM

Proposed Chiral ERA Decision Tree

0 62.5 125 250 500 10000

10

20

30

40

50F0F1

[EE2] (g L-1)

*

Nor

mal

ized

Mea

n V

itel

lin

(µg

orga

nism

-1)

0 62.5 125 250 500 10000

10

20

30

40F0F1

Mea

n E

cdys

one

(pg

orga

nism

-1)

[EE2] (g L-1)

[EE2] (g L-1)

0 62.5 125 250 500 1000

Intr

insi

c R

ate

of P

opul

atio

n G

row

th

0.0

0.2

0.4

0.6

0.8

1.0F0F1

Multigenerational Daphnia magna Responses to 17α-ethinylestradiol

Clubbs & Brooks 2007. EES

Model Organism and MOA Matters

4. Mode of Action


The 17α-ethinylestradiol Example

Kidd et al. 2007. PNAS USA

But High Potency in Fish….

“Intelligent” Toxicology

Bradbury, Feijtel, van Leeuwen. 2004. ES&T

“Intelligent” Ecotoxicology?

Ankley et al. 2010 ET&C

Some General Research Questions

1. How can hazard be estimated for compounds with limited exposure data?

2. How does one select a model for a specific endpoint or chemical class when multiple models exist?

3. Which chemicals may required future studies of acute and chronic hazards?

More Efficient Risk Assessment?

Bradbury, Feijtel, van Leeuwen. 2004. ES&T

Kroes et al. 2005. Toxicological Sciences

Thresholds of Toxicological Concern

• Historically applied to food additives• Oral route only; applications to other routes of exposure may require additional effort

• 1.5 g/person/day considered safe• Some exceptions (e.g., genotoxic carcinogens)

• Several previous approaches to TTC• Broad spectrum • Structurally based

http://www.baylor.edu/CRASR

De Wolf et al. 2005. ETC

“….no evidence suggests that an ETNCaq,MOA1–3 of 0.1 μg/L is an unacceptablevalue.”

Aquatic Exposure Thresholds of No Concern?

Chemical toxicity distribution (CTD)

0.10.01

Concentration (log scale)

1 10 100 1000 10000

Pe

rce

nt r

an

k

0.1

10

30

50

70

90

99

99.9

99.99

1st centile

5th centile

Toxicological benchmark concentration (TBC)

Criterion concentration or predicted environmental concentration (PEC)

Probability of finding a compound ≤ the criterion concentration value or PEC

A Chemical Toxicity Distribution

Probabilistic Hazard Assessment

ON

CD3

http://www.baylor.edu/CRASR

Acute Toxicity(Rat LD50 mg/kg) (Fish LC50 mg/L)

10-3 10-2 10-1 100 101 102 103 104 105

Per

cen

t R

ank

0.001

0.01

0.1

1

10

305070

90

99

99.9

99.99

fish ( ) r2 = 0.96

rat ( ) r2 = 0.92Wa

Wa ClCl

Ib

IbPr

Pr

Flu

Flu

EryEry EE

EE

Fam

Fam

- Only 5% of drugs predicted to be toxic to fish below 0.84 mg/L and rodents below 33.5 mg/kg

Berninger and Brooks. 2010. Toxicol Lett

Predicting Toxicity for a Broad Group

Predicting Toxicity for a Narrower Group

- Only 5% of surfactants predicted to be acutely toxic to Daphnia magna below 0.354 mg/L

Williams, Berninger and Brooks. 2011. ETC

Parabens: Antimicrobial Agents

Dobbins et al. 2009. ETC

Predicting Toxicity for a Specific Class

- Only 5% of parabens predicted to adversely affect fish survival and growth below 0.74 μg/L and 0.37 μg/L, respectively

log P

1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6

log

mea

n LC

50 (

mg

L-1

)

0.4

0.6

0.8

1.0

1.2

1.4

1.6

1.8

2.0

2.2

Fathead MinnowDaphnia magna

R2 = 0.88

R2 = 0.99

Methylparaben(log P = 1.87)

Benzylparaben(log P = 3.64)

Paraben Acute Toxicity MOA: Narcosis?

Dobbins et al. 2009. ETC

Predicting Toxicity for a Specific Class

Predicting Toxicity for a Specific MOA

Acute Toxicity of Acetylcholinesterase Inhibitors


- Only 5% of AChEIs predicted to be acutely toxic to Daphnia magna and Pimephales promelas below 0.188 μg/L and 65.07 μg/L, respectively

Using Probabilistic Hazard Approaches to Prioritize Chemical Safety Studies:

Application to REACH


Current Challenge: Lack of Safety Data

• Lack of safety information for many chemicals

• Current approach is retrospective

• Can we take prospective approaches?

Principles of Green Chemistry

Warner, J.; Anastas, P. Green Chemistry: Theory and Practice, 1993.

9. Use catalysts

Green Chemistry Principle #4Chemical products should be designed to

preserve efficacy of function while reducing toxicity and other environmental hazards.

Chemical products should be designed to preserve efficacy of function while reducing toxicity and other environmental hazards.

Warner, J.; Anastas, P. Green Chemistry: Theory and Practice, 1993.

Chemistry & EngineeringChemistry & Engineering

Toxicology & BiochemistryToxicology & Biochemistry

Ecology & Env. ScienceEcology &

Env. Science

Sustainable Molecular Design Guidelines?

Design Guidelines for Reduced Aquatic Toxicity: Standardized Responses

• 70-80% of the compounds that have low acute aquatic toxicity have a defined range of values for octanol-water partition coefficient, logPo/w, and ΔE (LUMO-HOMO energy).

• Compounds with logPo/w values < 2 and ΔE > 9 eV are significantly more likely to have low acute aquatic toxicity

• These design guidelines closely extend to standardized aquatic chronic/subchronic effects.

Voutchkova et al 2011, 2012 Green Chem

What if we employed sustainable molecular design for commodity chemicals?

1) What might be the likelihood of encountering industrial chemicals exceeding established US EPA toxicological categories of concern?

2) What could be the likelihood of exceeding these toxicological categories if chemical design guidelines were followed in the future?

Design Guidelines for Reduced Acute Aquatic Toxicity

Fathead minnowP. promelasLC50, 96-h assay

671 chemicals

Japanese medaka Daphnia magna Green algaeO. latipes P. subcapitataLC50, 96-h assay EC50, 48-h assay EC50, 72-h

285 chemicals 363 chemicals 300 chemicals

LC50/EC50: 0 – 1 mg/L

LC50/EC50: 0 – 1 mg/L

LC50/EC50: 1 – 100

mg/L

LC50/EC50: 1 – 100

mg/L

LC50/EC50: 100 – 500

mg/L

LC50/EC50: 100 – 500

mg/L

LC50/EC50: > 500 mg/L

LC50/EC50: > 500 mg/L

4 categories based on EPA toxicological categories

Voutchkova 2011 Green Chem.; Russom 1997 ETC; Japan Ministry of Environment

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106

0.10.20.5

125

102030

50

708090959899

99.899.9

What might be the likelihood of encountering industrial chemicals exceeding established US

EPA toxicological categories?All chemicals

14.5

14.416

55.1

High: 0-1 mg/LModerate 1-100 mg/LLow 100-500 mg/LNone >500 mg/L

AlldElog PBoth

Per

cent

Ran

k

P. promelas 96 hr. LC50 mg/L

All chemicals (n=570)

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106

0.10.20.5

125

102030

50

708090959899

99.899.9

What could be the likelihood of exceeding these toxicological categories if chemical design

guidelines were followed in the future?


AlldElog PBoth

Per

cent

Ran

k


All chemicals

14.5

14.416

55.1

Chemicals with dE above 9 eV (n=408)

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106

0.10.20.5

125

102030

50

708090959899

99.899.9




AlldElog PBoth

Per

cent

Ran

k


All chemicals

14.5

14.416

55.1

Chemicals with logP below 2 (n=299)

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106

0.10.20.5

125

102030

50

708090959899

99.899.9




Following guidelines

42.7 3.3 %

30.623.4All

dElog PBoth

Per

cent

Ran

k


All chemicals

14.5

14.416

55.1

Chemicals with both dE above 9 and logP below 2 (n=233)

EC50 mg/L

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104

Per

cent

Ran

k

0.10.20.5

125

102030

50

708090959899

99.899.9

EC50 mg/L

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104

Per

cent

Ran

k

0.10.20.5

125

102030

50

708090959899

99.899.9

LC50 mg/L

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104 105 106

Per

cent

Ran

k

0.10.20.5

125

102030

50

708090959899

99.899.9

Alllog PdE Both

Extends to other models…

LC50 mg/L

10-5 10-4 10-3 10-2 10-1 100 101 102 103 104

Per

cent

Ran

k

0.10.20.5

125

102030

50

708090959899

99.899.9

P. promelas O. latipes

P. subcapitataD. magna

Projected Reduction in Chemicals Falling in High Toxicity Category?

• Acute– 11.2-20.7% reduction in chemicals classified as

“high” acute toxicity

– Guidelines are more successful at reducing toxicity in Daphnia than fish species (4.5-9.5%)

Ongoing Research– Exploring additional guidelines to understand

chemicals remaining in “high” toxicity category

– Working to identify sustainable molecular design guidelines for specific MOAs, or other model organisms and responses

– Further examine utility of these guidelines may be possible as additional toxicity data becomes available (e.g., REACH)

Some Parting Thoughts….

- Define toxicological endpoints, models well

- Ionization, Chirality, Nutrients = Uncertainty

- A priori understanding of MOA; AOPs

- Sustainable molecular design = prospective

- Probabilistic hazard assessment can support prioritization, sustainable design and read-across approaches

Thank You

Perspectives on Environmental Assessments of Chemicals Used in Consumer Products Bryan W. Brooks...

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